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Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.

Caputi A, Fuchs EC, Allen K, Le Magueresse C, Monyer H - PLoS ONE (2012)

Bottom Line: Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence.These changes were associated with an increased firing rate of pyramidal cells during ripples.These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

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Theta oscillations in GluA4HC−/− mice. (A) Representative examples of theta oscillations recorded during exploratory trials in control and GluA4HC−/− mice. Top trace: raw signal. Bottom trace: band-pass filtered (5–14 Hz) signal. (B) Mean power spectra in the theta frequency range when mice ran at different speed. The peak power and peak frequency was similar in the control and GluA4HC−/− mice. (C) Polar plot of the preferred theta phase and theta vector length of pyramidal cells in control and GluA4HC−/− mice. Each dot represents a neuron. Phase 0 is the positive-to-negative zero-crossing of the theta oscillation. The theta vector length of each cells is equal to the distance between the dot and the center of the plot. The short lines in the right-top corner indicate the mean preferred phase of the recorded neurons. (D) Mean theta vector length for all pyramidal cells in control and GluA4HC−/− mice. (E) Distribution of preferred theta phase for pyramidal cells in control and GluA4HC−/− mice. (F) Mean firing probability at different theta phases for pyramidal cells. (G–J) Same as C–F but for interneurons. Abbreviations: Int., interneurons; Pyr., pyramidal cells. **: p<0.005.
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pone-0037318-g005: Theta oscillations in GluA4HC−/− mice. (A) Representative examples of theta oscillations recorded during exploratory trials in control and GluA4HC−/− mice. Top trace: raw signal. Bottom trace: band-pass filtered (5–14 Hz) signal. (B) Mean power spectra in the theta frequency range when mice ran at different speed. The peak power and peak frequency was similar in the control and GluA4HC−/− mice. (C) Polar plot of the preferred theta phase and theta vector length of pyramidal cells in control and GluA4HC−/− mice. Each dot represents a neuron. Phase 0 is the positive-to-negative zero-crossing of the theta oscillation. The theta vector length of each cells is equal to the distance between the dot and the center of the plot. The short lines in the right-top corner indicate the mean preferred phase of the recorded neurons. (D) Mean theta vector length for all pyramidal cells in control and GluA4HC−/− mice. (E) Distribution of preferred theta phase for pyramidal cells in control and GluA4HC−/− mice. (F) Mean firing probability at different theta phases for pyramidal cells. (G–J) Same as C–F but for interneurons. Abbreviations: Int., interneurons; Pyr., pyramidal cells. **: p<0.005.

Mentions: Prominent theta oscillations were recorded from the CA1 pyramidal cell layer in control and GluA4HC−/− mice (Figure 5A). Power spectra were calculated as the mice ran at different speed intervals during exploratory trials (Figure 5B). The peak theta power or the mean peak theta frequency of the power spectra were not changed in GluA4HC−/− mice (Figure 5B and Figure S6, control n = 9 mice, GluA4HC−/− n = 12 mice), suggesting that the frequency and power of theta oscillations were normal in GluA4HC−/− mice. The burst theta frequency of pyramidal cells and interneurons, as assessed by their spike-time autocorrelation during theta epochs, was also similar in the two genotypes (Figure S6C–D, pyramidal cells, control n = 362 cells, GluA4HC−/− n = 324 cells, control: 115.16±0.70 ms, GluA4HC−/−: 114.83±0.65 ms, p = 0.16; interneurons, control n = 65 cells, GluA4HC−/− n = 41 cells, control: 113.22±1.99 ms, GluA4HC−/−: 117.83±1.73 ms, p = 0.40).


Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.

Caputi A, Fuchs EC, Allen K, Le Magueresse C, Monyer H - PLoS ONE (2012)

Theta oscillations in GluA4HC−/− mice. (A) Representative examples of theta oscillations recorded during exploratory trials in control and GluA4HC−/− mice. Top trace: raw signal. Bottom trace: band-pass filtered (5–14 Hz) signal. (B) Mean power spectra in the theta frequency range when mice ran at different speed. The peak power and peak frequency was similar in the control and GluA4HC−/− mice. (C) Polar plot of the preferred theta phase and theta vector length of pyramidal cells in control and GluA4HC−/− mice. Each dot represents a neuron. Phase 0 is the positive-to-negative zero-crossing of the theta oscillation. The theta vector length of each cells is equal to the distance between the dot and the center of the plot. The short lines in the right-top corner indicate the mean preferred phase of the recorded neurons. (D) Mean theta vector length for all pyramidal cells in control and GluA4HC−/− mice. (E) Distribution of preferred theta phase for pyramidal cells in control and GluA4HC−/− mice. (F) Mean firing probability at different theta phases for pyramidal cells. (G–J) Same as C–F but for interneurons. Abbreviations: Int., interneurons; Pyr., pyramidal cells. **: p<0.005.
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pone-0037318-g005: Theta oscillations in GluA4HC−/− mice. (A) Representative examples of theta oscillations recorded during exploratory trials in control and GluA4HC−/− mice. Top trace: raw signal. Bottom trace: band-pass filtered (5–14 Hz) signal. (B) Mean power spectra in the theta frequency range when mice ran at different speed. The peak power and peak frequency was similar in the control and GluA4HC−/− mice. (C) Polar plot of the preferred theta phase and theta vector length of pyramidal cells in control and GluA4HC−/− mice. Each dot represents a neuron. Phase 0 is the positive-to-negative zero-crossing of the theta oscillation. The theta vector length of each cells is equal to the distance between the dot and the center of the plot. The short lines in the right-top corner indicate the mean preferred phase of the recorded neurons. (D) Mean theta vector length for all pyramidal cells in control and GluA4HC−/− mice. (E) Distribution of preferred theta phase for pyramidal cells in control and GluA4HC−/− mice. (F) Mean firing probability at different theta phases for pyramidal cells. (G–J) Same as C–F but for interneurons. Abbreviations: Int., interneurons; Pyr., pyramidal cells. **: p<0.005.
Mentions: Prominent theta oscillations were recorded from the CA1 pyramidal cell layer in control and GluA4HC−/− mice (Figure 5A). Power spectra were calculated as the mice ran at different speed intervals during exploratory trials (Figure 5B). The peak theta power or the mean peak theta frequency of the power spectra were not changed in GluA4HC−/− mice (Figure 5B and Figure S6, control n = 9 mice, GluA4HC−/− n = 12 mice), suggesting that the frequency and power of theta oscillations were normal in GluA4HC−/− mice. The burst theta frequency of pyramidal cells and interneurons, as assessed by their spike-time autocorrelation during theta epochs, was also similar in the two genotypes (Figure S6C–D, pyramidal cells, control n = 362 cells, GluA4HC−/− n = 324 cells, control: 115.16±0.70 ms, GluA4HC−/−: 114.83±0.65 ms, p = 0.16; interneurons, control n = 65 cells, GluA4HC−/− n = 41 cells, control: 113.22±1.99 ms, GluA4HC−/−: 117.83±1.73 ms, p = 0.40).

Bottom Line: Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence.These changes were associated with an increased firing rate of pyramidal cells during ripples.These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

Show MeSH
Related in: MedlinePlus